Compounds Having CRTH2 Antagonist Activity

ABSTRACT

Compounds of general formula (I) wherein R is phenyl optionally substituted with one or more halo substituents; and their pharmaceutically acceptable salts, hydrates, solvates, complexes or prodrugs are useful in orally administrable compositions for the treatment of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis.

The present invention relates to compounds which are useful aspharmaceuticals, to methods for preparing these compounds, compositionscontaining them and their use in the treatment and prevention ofallergic diseases such as asthma, allergic rhinitis and atopicdermatitis and other inflammatory diseases mediated by prostaglandin D₂(PGD₂) or other agonists acting at the CRTH2 receptor on cells includingeosinophils, basophils and Th2 lymphocytes.

PGD₂ is an eicosanoid, a class of chemical mediator synthesised by cellsin response to local tissue damage, normal stimuli or hormonal stimulior via cellular activation pathways. Eicosanoids bind to specific cellsurface receptors on a wide variety of tissues throughout the body andmediate various effects in these tissues. PGD₂ is known to be producedby mast cells, macrophages and Th2 lymphocytes and has been detected inhigh concentrations in the airways of asthmatic patients challenged withantigen (Murray et al, (1986), N. Engl. J. Med. 315: 800-804).Instillation of PGD₂ into airways can provoke many features of theasthmatic response including bronchoconstriction (Hardy et al, (1984) N.Engl. J. Med. 311: 209-213; Sampson et al, (1997) Thorax 52: 513-518)and eosinophil accumulation (Emery et al, (1989) J. Appl. Physiol. 67:959-962).

The potential of exogenously applied PGD₂ to induce inflammatoryresponses has been confirmed by the use of transgenic miceoverexpressing human PGD₂ synthase which exhibit exaggeratedeosinophilic lung inflammation and Th2 cytokine production in responseto antigen (Fujitani et al, (2002) J. Immunol. 168: 443-449).

The first receptor specific for PGD₂ to be discovered was the DPreceptor which is linked to elevation of the intracellular levels ofcAMP. However, PGD₂ is thought to mediate much of its proinflammatoryactivity through interaction with a G protein-coupled receptor termedCRTH2 (chemoattractant receptor-homologous molecule expressed on Th2cells) which is expressed by Th2 lymphocytes, eosinophils and basophils(Hirai et al, (2001) J. Exp. Med. 193: 255-261, and EP0851030 andEP-A-1211513 and Bauer et al, EP-A-1170594). It seems clear that theeffect of PGD₂ on the activation of Th2 lymphocytes and eosinophils ismediated through CRTH2 since the selective CRTH2 agonists 13,14dihydro-15-keto-PGD₂ (DK-PGD₂) and 15R-methyl-PGD₂ can elicit thisresponse and the effects of PGD₂ are blocked by an anti-CRTH2 antibody(Hirai et al, 2001; Monneret et al, (2003) J. Pharmacol. Exp. Ther. 304:349-355). In contrast, the selective DP agonist BW245C does not promotemigration of Th2 lymphocytes or eosinophils (Hirai et al, 2001; Gervaiset al, (2001) J. Allergy Clin. Immunol. 108: 982-988). Based on thisevidence, antagonising PGD₂ at the CRTH2 receptor is an attractiveapproach to treat the inflammatory component of Th2-dependent allergicdiseases such as asthma, allergic rhinitis and atopic dermatitis.

EP-A-1170594 suggests that the method to which it relates can be used toidentify compounds which are of use in the treatment of allergic asthma,atopic dermatitis, allergic rhinitis, autoimmune, reperfusion injury anda number of inflammatory conditions, all of which are mediated by theaction of PGD₂ or other agonists at the CRTH2 receptor.

Compounds which bind to CRTH2 are taught in WO-A-03066046 andWO-A-03066047. These compounds are not new but were first disclosed,along with similar compounds, in GB 1356834, GB 1407658 and GB 1460348,where they were said to have anti-inflammatory, analgesic andantipyretic activity. WO-A-03066046 and WO-A-03066047 teach that thecompounds to which they relate are modulators of CRTH2 receptor activityand are therefore of use in the treatment or prevention of obstructiveairway diseases such as asthma, chronic obstructive pulmonary disease(COPD) and a number of other diseases including various conditions ofbones and joints, skin and eyes, GI tract, central and peripheralnervous system and other tissues as well as allograft rejection. Thesecompounds are all indole derivatives with an acetic acid substituent atthe 3-position of the indole ring.

PL 65781 and JP 43-24418 also relate to indole-3 acetic acid derivativeswhich are similar in structure to indomethacin and, like indomethacin,are said to have anti-inflammatory and antipyretic activity. Thus,although this may not have been appreciated at the time when thesedocuments were published, the compounds they describe are COXinhibitors, an activity which is quite different from that of thecompounds of the present invention. Indeed, COX inhibitors arecontraindicated in the treatment of many of the diseases and conditions,for example asthma and inflammatory bowel disease for which thecompounds of the present invention are useful, although they maysometimes be used to treat arthritic conditions.

There is further prior art which relates to indole-1-acetic acidcompounds, although these are not described as CRTH2 antagonists. Forexample WO-A-9950268, WO-A-0032180, WO-A-0151849 and WO-A-0164205 allrelate to compounds which are indole-1-acetic acid derivatives but thesecompounds are said to be aldose reductase inhibitors useful in thetreatment of diabetes mellitus (WO-A-9950268, WO-A-0032180 andWO-A-0164205) or hypouricemic agents (WO-A-0151849). There is nosuggestion in any of these documents that the compounds would be usefulfor the treatment of diseases and conditions mediated by PGD₂ or otherCRTH2 receptor agonists.

U.S. Pat. No. 4,363,912 relates to indole-1-acetic acid derivativeswhich are said to be inhibitors of thromboxane synthetase and to beuseful in the treatment of conditions such as thrombosis, ischaemicheart disease and stroke.

WO-A-9603376 relates to compounds which are said to be sPLA₂ inhibitorswhich are useful in the treatment of bronchial asthma and allergicrhinitis. These compounds all have amide or hydrazide substituents inplace of the carboxylic acid derivative of the compounds of the presentinvention.

JP 2001247570 relates to a method of producing a 3-benzothiazolylmethylindole acetic acid, which is said to be an aldose reductase inhibitor.

U.S. Pat. No. 4,859,692 relates to compounds which are said to beleukotriene antagonists useful in the treatment of conditions such asasthma, hay fever and allergic rhinitis as well as certain inflammatoryconditions such as bronchitis, atopic and ectopic eczema. Some of thecompounds of this document are indole-1-acetic acids but the sameauthors, in J. Med. Chem., 6(33), 1781-1790 (1990), teach that compoundswith an acetic acid group on the indole nitrogen do not have significantpeptidoleukotriene activity. In view of this, it is most surprising thatthe compounds of the present invention, which all have an acetic acidgroup on the indole nitrogen, are useful for treating conditions such asasthma, hay fever and allergic rhinitis.

U.S. Pat. No. 4,273,782 is directed to indole-1-acetic acid derivativeswhich are said to be useful in the treatment of conditions such asthrombosis, ischaemic heart disease, stroke, transient ischaemic attack,migraine and the vascular complications of diabetes. There is no mentionin the document of conditions mediated by the action of PGD₂ or otheragonists at the CRTH2 receptor.

U.S. Pat. No. 3,557,142 relates to 3-substituted-1-indole carboxylicacids and esters which are said to be useful in the treatment ofinflammatory conditions.

WO-A-03/097598 relates to compounds which are CRTH2 receptorantagonists. They do not have an aromatic substituent at the indole-3position.

Cross et al, J. Med. Chem. 29, 342-346 (1986) relates to a process forpreparing indole-1-acetic acid derivatives from the correspondingesters. The compounds to which it relates are said to be inhibitors ofthromboxane synthetase.

EP-A-0539117 relates to indole-1-acetic acid derivatives which areleukotriene antagonists

US 2003/0153751 relates to indole-1-acetic acid derivatives which aresPLA₂ inhibitors. However, all of the exemplified compounds have bulkysubstituents at the 2- and 5-positions of the indole system and aretherefore very different from the compounds of the present invention.

US 2004/011648 discloses indole-1-acetic acid derivatives which areinhibitors of PAI-1. There is no suggestion that the compounds mighthave CRTH2 antagonist activity.

WO 2004/058164 relates to compounds which are said to be asthma andallergic inflammation modulators. The only compounds for which activityis demonstrated are entirely different in structure from theindole-1-acetic acid derivatives of the present invention.

Compounds which bind to the CRTH2 receptor are disclosed inWO-A-03/097042 and WO-A-03/097598. These compounds are indole aceticacids but in WO-A-03/097042 the indole system is fused at the 2-3positions to a 5-7 membered carbocyclic ring. In WO-A-03/097598 there isa pyrrolidine group at the indole 3-position.

WO-A-03/101981, WO-A-03/101961 and WO-A-2004/007451 all relate toindole-1-acetic acid derivatives which are said to be CRTH2 antagonistsbut which differ in structure from the compounds of general formula (I)because there is no spacer or an —S— or —SO₂— group at to the indole3-position in place of the CH₂ group of the compounds of the presentinvention as described below.

WO-A-2005/019171 also describes indole-1-acetic acid derivatives whichare said to be CRTH2 antagonists and which are said to be useful for thetreatment of various respiratory diseases. These compounds all have asubstituent which is linked to the indole-3 position by an oxygenspacer.

WO-A-2005/094816 again describes indole-1-acetic acid compounds, thistime with an aliphatic substituent at the 3-position of the indole ring.The compounds are said to be CRTH2 antagonists.

WO-A-2006/034419 relates to CRTH2 antagonist indole compounds which havea heterocyclic or heteroaromatic substituent directly linked to the3-position of the indole ring system.

In our earlier application, WO-A-2005/044260, we describe compoundswhich are antagonists of PGD₂ at the CRTH2 receptor. These compounds areindole-1-acetic acid derivatives substituted at the 3-position with agroup CR⁸R⁹, wherein R⁹ is hydrogen or alkyl and R⁸ is an aromaticmoiety which may be substituted with one or more substituents. Thecompounds described in this document are potent antagonists in vitro ofPGD₂ at the CRTH2 receptor. However, we have found that when tested invivo, the pharmacokinetic profile of some compounds is not optimal andtheir potency in the whole blood eosinophil shape change test, whichgives an indication of the likely in vivo activity of the compounds, isoften somewhat less than might have been expected from the in vitrobinding results.

Surprisingly, however, we have found that by making changes to the R⁸group of the compounds of WO-A-2005/044260 we are able to achieveimprovements in the in vitro whole blood eosinophil shape change potencyand the in vivo inhibition of DK-PGD₂-induced blood eosinophilia and thepharmacokinetic profile on oral administration to a subject.

The present invention therefore relates to novel compounds which bind toCRTH2 and which are therefore useful in the treatment of diseases andconditions mediated by the activity of PGD₂ at the CRTH2 receptor.

In the present invention there is provided a compound of general formula(I)

wherein R is phenyl optionally substituted with one or more halosubstituents; or a pharmaceutically acceptable salt, hydrate, solvate,complex or prodrug thereof.

The compounds of general formula (I) are antagonists at the CRTH2receptor and are useful in the treatment of conditions which aremediated by PGD₂ or other agonists binding to CRTH2. These includeallergic diseases, asthmatic conditions and inflammatory diseases,examples of which are asthma, including allergic asthma, bronchialasthma, exacerbations of asthma and related allergic diseases caused byviral infection, particularly those exacerbations caused by rhinovirusand respiratory syncytial virus intrinsic, extrinsic, exercise-induced,drug-induced and dust-induced asthma, treatment of cough, includingchronic cough associated with inflammatory and secretory conditions ofthe airways and iatrogenic cough, acute and chronic rhinitis, includingrhinitis medicamentosa, vasomotor rhinitis, perennial allergic rhinitis,seasonal allergic rhinitis, nasal polyposis, acute viral infectionincluding common cold, infection due to respiratory syncytial virus,influenza, coronavirus and adenovirus, atopic dermatitis, contacthypersensitivity (including contact dermatitis), eczematous dermatitis,phyto dermatitis, photo dermatitis, sebhorroeic dermatitis, dermatitisherpetiformis, lichen planus, lichen sclerosis et atrophica, pyodermagangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus,pemphigoid, epidermolysis bullosa urticaria, angioedema, vasculitides,toxic erythemas, cutaneous eosinophilias, alopecia areata, male-patternbaldness, Sweet's syndrome, Weber-Christian syndrome, erythemamultiforme, cellulitis, panniculitis, cutaneous lymphomas, non-melanomaskin cancer and other dysplastic lesions; blepharitis conjunctivitis,especially allergic conjunctivitis, anterior and posterior uveitis,choroiditis, autoimmune, degenerative or inflammatory disordersaffecting the retina, ophthalmitis; bronchitis, including infectious andeosinophilic bronchitis, emphysema, bronchiectasis, farmer's lung,hypersensitivity pneumonitis, idiopathic interstitial pneumonias,complications of lung transplantation, vasculitic and thromboticdisorders of the lung vasculature, pulmonary hypertension, foodallergies, gingivitis, glossitis, periodontitis, oesophagitis includingreflux, eosinophilic gastroenteritis, proctitis, pruris ani, celiacdisease, food-related allergies, inflammatory bowel disease, ulcerativecolitis and Crohn's disease, mastocytosis and also other CRTH2-mediateddiseases, for example autoimmune diseases such as hyper IgE syndrome,Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetesmellitus, idiopathic thrombocytopaenic purpura, eosinophilic paschiitis,antiphospholipid syndrome and systemic lupus erythematosus, AIDS,leprosy, Sezary syndrome, paraneoplastic syndrome, mixed andundifferentiated connective tissue diseases, inflammatory myopathiesincluding dermatomyositis and polymyositis, polymalgia rheumatica,juvenile arthritis, rheumatic fever, vasculitides including giant cellarteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritisnodosa, microscopic polyarteritis, temporal arteritis, myastheniagravic, acute and chronic pain, neuropathic pain syndromes,neurodegeneration, central and peripheral nervous system complicationsof malignant, infectious or autoimmune processes, low back pain,familial Mediterranean Fever, Muckle-Wells syndrome, Familial Hibernianfever, Kikuchi disease, psoriasis, acne, multiple sclerosis, allograftrejection, reperfusion injury, chronic obstructive pulmonary disease, aswell as rheumatoid arthritis, Still's disease, ankylosing spondylitis,reactive arthritis, undifferentiated spondarthropathy, psoriaticarthritis, septic arthritis and other infection-related arthopathies andbone disorders and osteoarthritis; acute and chronic crystal-inducedsynovitis including urate gout, calcium pyrophosphate depositiondisease, calcium paptite related tendon syndrome and synovialinflammation, Behcet's disease, primary and secondary Sjogren's syndromesystemic sclerosis and limited scleroderma; hepatitis, cirrhosis of theliver, cholecystitis, pancreatitis, nephritis, nephritic syndrome,cystitis and Hunner's ulcer, acute and chronic urethritis, prostatitis,epididymitis, oophoritis, salpingitis, vulvo-vaginitis, Peyronie'sdisease, erectile dysfunction, Alzheimer's disease and other dementingdisorders; pericarditis, myocarditis, inflammatory and auto-immunecardiomyopathies including myocardial sarcoid, ischaemic reperfusioninjuries, endocarditis, valvulitis, aortitis, phlebitis, thrombosis,treatment of common cancers and fibrotic conditions such as idiopathicpulmonary fibrosis including cryptogenic fibrosing alveolitis, keloids,excessive fibrotic scarring/adhesions post surgery, liver fibrosisincluding that associated with hepatitis B and C, uterine fibroids,sarcoidosis, including neurosarcoidosis, scleroderma, kidney fibrosisresulting from diabetes, fibrosis associated with RA, atherosclerosis,including cerebral atherosclerosis, vasculitis, myocardial fibrosisresulting from myocardial infarction, cystic fibrosis, restenosis,systemic sclerosis, Dupuytren's disease, fibrosis complicatinganti-neoplastic therapy and chronic infection including tuberculosis andaspergillosis and other fungal infections, CNS fibrosis following strokeor the promotion of healing without fibrotic scarring.

The compounds are particularly useful for the treatment or prevention ofallergic asthma, perennial allergic rhinitis, seasonal allergicrhinitis, atopic dermatitis, contact hypersensitivity (including contactdermatitis), conjunctivitis, especially allergic conjunctivitis,eosinophilic bronchitis, food allergies, eosinophilic gastroenteritis,inflammatory bowel disease, ulcerative colitis and Crohn's disease,mastocytosis, pain, neurodegenerative diseases and also otherPGD₂-mediated diseases, for example autoimmune diseases such as hyperIgE syndrome and systemic lupus erythematus, psoriasis, acne, multiplesclerosis, allograft rejection, reperfusion injury, chronic obstructivepulmonary disease, as well as rheumatoid arthritis, psoriatic arthritisand osteoarthritis.

The improved potency in the whole blood eosinophil shape change test andpharmacokinetic profile of the compounds of general formula (I) isparticularly surprising since some of the compounds of WO-A-2005/044260,which are close in structure to the compounds of general formula (I) donot have these advantageous properties. In particular, the compound ofExample 17 of WO-A-2005/044260 is similar to the compounds of thepresent invention and might have been expected to have similarproperties. However, the replacement of the methylsulfonyl group at the4-position of the benzene ring in Example 17 of WO-A-2005/044260 withthe SO₂R group at the 2-position of the benzene ring in the compounds offormula (I) has a significant effect on the pharmacokinetics and theactivity of the compounds because when Compound 17 of WO-A-2005/044260is administered orally, its pharmacokinetic profile in vivo is lessfavourable than that of the compounds of general formula (I).

In addition for many of the compounds of WO-A-2005/044260, we have foundthat their in vitro whole blood eosinophil shape change activity isoften less than might have been expected from their in vitro activity asmeasured by radioligand binding experiments to the CRTH2 receptor.

Furthermore, the improvement in activity is very specific to the groupof compounds of general formula (I) as compounds which are even moreclosely related than those of WO-A-2005/044260 do not have suchfavourable properties. For example, the analogues of general formula (I)in which the SO₂R group is at the 3- or 4-position of the benzene ringare less active in in vitro whole blood eosinophil shape change tests.

In the present specification “C₁-C₆ alkyl” refers to a straight orbranched saturated hydrocarbon chain having one to six carbon atoms andoptionally substituted with one or more halo substituents or with one ormore C₃-C₇ cycloalkyl groups. Examples include methyl, ethyl, n-propyl,isopropyl, t-butyl, n-hexyl, trifluoromethyl, 2-chloroethyl,methylenecyclopropyl, methylenecyclobutyl, methylenecyclobutyl andmethylenecyclopentyl.

“C₁-C₄ alkyl” and “C₁-C₁₈ alkyl” have similar meanings except that theycontain from one to four and from one to eighteen carbon atomsrespectively.

C₃-C₇ cycloalkyl refers to a saturated 3 to 7 membered carbocyclic ring.Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

In the present specification, “halo” refers to fluoro, chloro, bromo oriodo.

The terms “aromatic moiety” and “aryl” in the context of the presentspecification refer to an aromatic ring system having from 5 to 14 ringcarbon atoms and containing up to three rings. Examples of aromaticmoieties are benzene and naphthalene. Aryl groups may be substitutedwith one or more substituents chosen from halo, C₁-C₆ alkyl, C₁-C₆alkoxy, a 5-7-membered heterocyclic ring or SO₂R⁹ where R⁹ is as definedabove.

Appropriate pharmaceutically and veterinarily acceptable salts of thecompounds of general formulae (I) and (II) include basic addition saltssuch as sodium, potassium, calcium, aluminum, zinc, magnesium and othermetal salts as well as choline, diethanolamine, ethanolamine, ethyldiamine and other well known basic addition salts.

Where appropriate, pharmaceutically or veterinarily acceptable salts mayalso include salts of organic acids, especially carboxylic acids,including but not limited to acetate, trifluoroacetate, lactate,gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate,alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate,glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate,fumarate, nicotinate, pamoate, pectinate, 3-phenylpropionate, picrate,pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate,undecanoate and succinate, organic sulfonic acids such asmethanesulfonate, ethanesulfonate, 2-hydroxyethane sulfonate,camphorsulfonate, 2-naphthalenesulfonate, benzenesulfonate,p-chlorobenzenesulfonate and p-toluenesulfonate; and inorganic acidssuch as hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate,hemisulfate, thiocyanate, persulfate, phosphoric and sulfonic acids.

Salts which are not pharmaceutically or veterinarily acceptable maystill be valuable as intermediates.

Prodrugs are any covalently bonded compounds which release the activeparent drug according to general formula (I) in vivo. Examples ofprodrugs include alkyl esters of the compounds of general formula (I),for example the esters of general formula (II) below.

If a chiral centre or another form of isomeric centre is present in acompound of the present invention, all forms of such isomer or isomers,including enantiomers and diastereoisomers, are intended to be coveredherein. Compounds of the invention containing a chiral centre may beused as a racemic mixture, an enantiomerically enriched mixture, or theracemic mixture may be separated using well-known techniques and anindividual enantiomer may be used alone.

In the compounds of general formula (I), it is preferred that the phenylgroup R is unsubstituted or is substituted with a single halosubstituent, usually fluoro or chloro, which is generally at the4-position of the phenyl group R.

Among the most preferred compounds are the following:

-   2-{5-Fluoro-2-methyl-3-[2-(phenylsulfonyl)benzyl]-1H-indol-1-yl}acetic    acid;-   2-{3-[2-(4-chlorophenylsulfonyl)benzyl]-5-fluoro-2-methyl-1H-indol-1-yl}acetic    acid;-   2-{5-Fluoro-3-[2-(4-fluorophenylsulfonyl)benzyl]-2-methyl-1H-indol-1-yl}acetic    acid;

or the C₁-C₆ alkyl, aryl, (CH₂)_(m)OC(═O)C₁-C₆alkyl, (CH₂)_(m)N(R¹¹)₂,CH((CH₂)_(m)O(C═O)R¹²)₂ esters of any of the above; wherein

-   -   m is 1 or 2;    -   R¹¹ is hydrogen or methyl;    -   R¹² is C₁-C₁₈ alkyl.

In a further aspect of the present invention, there is provided acompound of general formula (II):

wherein R is as defined for general formula (I); and

R¹ is C₁-C₆ alkyl, aryl, (CH₂)_(m)OC(═O)C₁-C₆alkyl, (CH₂)_(m)N(R¹¹)₂,CH((CH₂)_(m)O(C═O)R¹²)₂;

-   -   m is 1 or 2;    -   R¹¹ is hydrogen or methyl;    -   R¹² is C₁-C₁₈ alkyl.

Compounds of general formula (II) are novel and may be used as prodrugsfor compounds of general formula (I). When the compound of generalformula (II) acts as a prodrug, it is later transformed to the drug bythe action of an esterase in the blood or in a tissue of the patient.

Examples of particularly suitable R¹ groups when the compound of generalformula (II) is used as a prodrug include:

methyl, ethyl, propyl, phenyl, CH₂OC(═O)tBu, CH₂CH₂N(Me)₂ CH₂CH₂NH₂ orCH(CH₂O(C═O)R¹²)₂ wherein R¹² is as defined above.

In addition to their use as prodrugs, compounds of formula (II) whereinR¹ is C₁-C₆ alkyl may be used in a process for the preparation of acompound of general formula (I), the process comprising reacting thecompound of general formula (II) with a base such as sodium hydroxide orlithium hydroxide. The reaction may take place in an aqueous solvent oran organic solvent or a mixture of the two. A typical solvent used forthe reaction is a mixture of tetrahydrofuran and water.

Compounds of general formula (II) may be prepared from compounds ofgeneral formula (III):

wherein R¹ is as defined in general formula (II); by reaction with acompound of general formula (IV):

wherein R is as defined for general formula (I);

under acidic reductive alkylation conditions.

Compounds of general formulae (III) are readily available or can beprepared by methods well known to those skilled in the art.

Aldehydes of general formula (IV) can be prepared by deprotecting anacetal of general formula (V)

wherein R is as defined for general formula (I). Deprotection may beachieved by reaction with an aqueous acid, for example sulphuric acid,followed by neutralisation with a base, typically solid potassiumcarbonate. The reaction may be carried out at 0 to 40° C., typically atroom temperature.

Compounds of general formula (V) may be prepared by the oxidation of acompound of general formula (VI)

wherein R is as defined for general formula (I). The oxidation of thesulfide group can be achieved using an excess amount of an oxidisingagent such as chloroperoxybenzoic acid. The reaction mixture may becooled initially, for example to −5 to 5° C. and then allowed to warm,typically to room temperature.

An acetal of general formula (VI) may be prepared by protecting analdehyde of general formula (VII)

wherein R is as defined for general formula (I). The protection may beachieved by reaction with trimethylorthoformate and p-toluene sulfonicacid in dry conditions and under an inert atmosphere followed by sodiummethoxide in methanol.

Compounds of general formula (VII) are commercially available.Alternatively, they can be prepared by reacting a compound of generalformula (VIII):

R—SH   (VIII)

where R is as defined for general formula (I) with 2-fluorobenzaldehyde.The reaction may be carried out under mildly basic conditions in a polarsolvent such as DMSO and under an inert atmosphere at a temperature offrom 80 to 110° C.

Compounds of general formula (VIII) are commercially available or may beprepared by methods well known to those of skill in the art.

Another route to compounds of general formula (VII) as defined above isvia the formylation of a compound of general formula (X):

where R is as defined for general formula (I);

using n-butyl lithium and dimethylformamide (DMF) in an organic solventsuch as tetrahydrofuran.

Typically, the reaction is carried out under an inert atmosphere, forexample nitrogen, cooled to a temperature of about −78° C. whilereacting with the n-butyl lithium and allowed to warm to roomtemperature after the addition of the DMF.

Compounds of general formula (X) may be prepared by reacting2-bromothiophenol with a compound of general formula (XI):

R—X   (XI)

Where R is as defined for general formula (I) and X is a leaving group,particularly a halo group such as chloro or bromo.

The reaction may be carried out in the presence of a base, for examplecaesium carbonate and at a temperature of 20-50° C., typically 40° C.

An alternative route to compounds of general formula (IV) is by reactionof sodium salts of general formula (IX):

R—SO₂Na   (IX)

wherein R is as defined for general formula (I) with2-fluorobenzaldehyde. The reaction may be carried out in a solvent suchas dimethylsulfoxide at elevated temperature, typically 80 to 110° C.The reaction may take several days to go to completion.

Sodium salts of general formula (IX) are commercially available.

Compounds of general formula (IV) may also be prepared directly fromcompounds of general formula (VII) without the need for the protectionand deprotection steps. In this procedure a cooled oxidising agent suchas meta chloroperoxybenzoic acid may be added to the compound of generalformula (VII), typically with cooling to about −5 to 5° C. The reactionmixture may be allowed to warm to 15 to 30° C., usually roomtemperature, and then reacted with sodium metabisulfite.

As mentioned above, some compounds of general formula (VII) arecommercially available.

Compounds of general formula (I) are CRTH2 receptor antagonists andcompounds of general formula (II) are prodrugs for compounds of generalformula (I). Compounds of general formulae (I) and (II) are thereforeuseful in a method for the treatment of diseases and conditions mediatedby PGD₂ or other agonists at the CRTH2 receptor, the method comprisingadministering to a patient in need of such treatment a suitable amountof a compound of general formula (I) or (II).

In a third aspect of the invention, there is provided a compound ofgeneral formula (I) or (II) for use in medicine, particularly for use inthe treatment or prevention of diseases and conditions mediated by PGD₂or other CRTH2 receptor agonists.

Furthermore, there is also provided the use of a compound of generalformula (I) or (II) in the preparation of an agent for the treatment orprevention of diseases and conditions mediated by CRTH2 receptoragonists, particularly PGD₂.

As mentioned above, such diseases and conditions include allergicdiseases, asthmatic conditions and inflammatory diseases, examples ofwhich are asthma, including allergic asthma, bronchial asthma,intrinsic, extrinsic, exercise-induced, drug-induced and dust-inducedasthma, treatment of cough, including chronic cough associated withinflammatory and secretory conditions of the airways and iatrogeniccough, acute and chronic rhinitis, including rhinitis medicamentosa,vasomotor rhinitis, perennial allergic rhinitis, seasonal allergicrhinitis, nasal polyposis, acute viral infection including common cold,infection due to respiratory syncytial virus, influenza, coronavirus andadenovirus, atopic dermatitis, contact hypersensitivity (includingcontact dermatitis), eczematous dermatitis, phyto dermatitis, photodermatitis, sebhorroeic dermatitis, dermatitis herpetiformis, lichenplanus, lichen sclerosis et atrophica, pyoderma gangrenosum, skinsarcoid, discoid lupus erythematosus, pemphigus, pemphigoid,epidermolysis bullosa urticaria, angioedema, vasculitides, toxicerythemas, cutaneous eosinophilias, alopecia areata, male-patternbaldness, Sweet's syndrome, Weber-Christian syndrome, erythemamultiforme, cellulitis, panniculitis, cutaneous lymphomas, non-melanomaskin cancer and other dysplastic lesions; blepharitis conjunctivitis,especially allergic conjunctivitis, anterior and posterior uveitis,choroiditis, autoimmune, degenerative or inflammatory disordersaffecting the retina, ophthalmitis; bronchitis, including infectious andeosinophilic bronchitis, emphysema, bronchiectasis, farmer's lung,hypersensitivity pneumonitis, idiopathic interstitial pneumonias,complications of lung transplantation, vasculitic and thromboticdisorders of the lung vasculature, pulmonary hypertension, foodallergies, gingivitis, glossitis, periodontitis, oesophagitis includingreflux, eosinophilic gastroenteritis, proctitis, pruris ani, celiacdisease, food-related allergies, inflammatory bowel disease, ulcerativecolitis and Crohn's disease, mastocytosis and also other CRTH2-mediateddiseases, for example autoimmune diseases such as hyper IgE syndrome,Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetesmellitus, idiopathic thrombocytopaenic purpura, eosinophilic paschiitis,antiphospholipid syndrome and systemic lupus erythematosus, AIDS,leprosy, Sezary syndrome, paraneoplastic syndrome, mixed andundifferentiated connective tissue diseases, inflammatory myopathiesincluding dermatomyositis and polymyositis, polymalgia rheumatica,juvenile arthritis, rheumatic fever, vasculitides including giant cellarteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritisnodosa, microscopic polyarteritis, temporal arteritis, myastheniagravic, acute and chronic pain, neuropathic pain syndromes,neurodegeneration, central and peripheral nervous system complicationsof malignant, infectious or autoimmune processes, low back pain,familial Mediterranean Fever, Muckle-Wells syndrome, Familial Hibernianfever, Kikuchi disease, psoriasis, acne, multiple sclerosis, allograftrejection, reperfusion injury, chronic obstructive pulmonary disease, aswell as rheumatoid arthritis, Still's disease, ankylosing spondylitis,reactive arthritis, undifferentiated spondarthropathy, psoriaticarthritis, septic arthritis and other infection-related arthopathies andbone disorders and osteoarthritis; acute and chronic crystal-inducedsynovitis including urate gout, calcium pyrophosphate depositiondisease, calcium paptite related tendon syndrome and synovialinflammation, Behcet's disease, primary and secondary Sjogren's syndromesystemic sclerosis and limited scleroderma; hepatitis, cirrhosis of theliver, cholecystitis, pancreatitis, nephritis, nephritic syndrome,cystitis and Hunner's ulcer, acute and chronic urethritis, prostatitis,epididymitis, oophoritis, salpingitis, vulvo-vaginitis, Peyronie'sdisease, erectile dysfunction, Alzheimer's disease and other dementingdisorders; pericarditis, myocarditis, inflammatory and auto-immunecardiomyopathies including myocardial sarcoid, ischaemic reperfusioninjuries, endocarditis, valvulitis, aortitis, phlebitis, thrombosis,treatment of common cancers and fibrotic conditions such as idiopathicpulmonary fibrosis including cryptogenic fibrosing alveolitis, keloids,excessive fibrotic scarring/adhesions post surgery, liver fibrosisincluding that associated with hepatitis B and C, uterine fibroids,sarcoidosis, including neurosarcoidosis, scleroderma, kidney fibrosisresulting from diabetes, fibrosis associated with RA, atherosclerosis,including cerebral atherosclerosis, vasculitis, myocardial fibrosisresulting from myocardial infarction, cystic fibrosis, restenosis,systemic sclerosis, Dupuytren's disease, fibrosis complicatinganti-neoplastic therapy and chronic infection including tuberculosis andaspergillosis and other fungal infections, and CNS fibrosis followingstroke. The compounds are also of use in the promotion of healingwithout fibrotic scarring.

The compounds of general formula (I) or (II) must be formulated in anappropriate manner depending upon the diseases or conditions they arerequired to treat.

Therefore, in a further aspect of the invention there is provided apharmaceutical composition comprising a compound of general formula (I)or (II) together with a pharmaceutical excipient or carrier. Otheractive materials may also be present, as may be considered appropriateor advisable for the disease or condition being treated or prevented.

The carrier, or, if more than one be present, each of the carriers, mustbe acceptable in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipient.

The formulations include those suitable for oral, rectal, nasal,bronchial (inhaled), topical (including eye drops, buccal andsublingual), vaginal or parenteral (including subcutaneous,intramuscular, intravenous and intradermal) administration and may beprepared by any methods well known in the art of pharmacy.

The route of administration will depend upon the condition to be treatedbut preferred compositions are formulated for oral, nasal, bronchial ortopical administration.

The composition may be prepared by bringing into association the abovedefined active agent with the carrier. In general, the formulations areprepared by uniformly and intimately bringing into association theactive agent with liquid carriers or finely divided solid carriers orboth, and then if necessary shaping the product. The invention extendsto methods for preparing a pharmaceutical composition comprisingbringing a compound of general formula (I) or (II) in conjunction orassociation with a pharmaceutically or veterinarily acceptable carrieror vehicle.

Formulations for oral administration in the present invention may bepresented as: discrete units such as capsules, sachets or tablets eachcontaining a predetermined amount of the active agent; as a powder orgranules; as a solution or a suspension of the active agent in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water in oil liquid emulsion; or as a bolus etc.

For compositions for oral administration (e.g. tablets and capsules),the term “acceptable carrier” includes vehicles such as commonexcipients e.g. binding agents, for example syrup, acacia, gelatin,sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose,ethylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers,for example corn starch, gelatin, lactose, sucrose, microcrystallinecellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride andalginic acid; and lubricants such as magnesium stearate, sodium stearateand other metallic stearates, glycerol stearate stearic acid, siliconefluid, talc waxes, oils and colloidal silica. Flavouring agents such aspeppermint, oil of wintergreen, cherry flavouring and the like can alsobe used. It may be desirable to add a colouring agent to make the dosageform readily identifiable. Tablets may also be coated by methods wellknown in the art.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active agent in a free flowingform such as a powder or granules, optionally mixed with a binder,lubricant, inert diluent, preservative, surface-active or dispersingagent. Moulded tablets may be made by moulding in a suitable machine amixture of the powdered compound moistened with an inert liquid diluent.The tablets may optionally be coated or scored and may be formulated soas to provide slow or controlled release of the active agent.

Other formulations suitable for oral administration include lozengescomprising the active agent in a flavoured base, usually sucrose andacacia or tragacanth; pastilles comprising the active agent in an inertbase such as gelatin and glycerin, or sucrose and acacia; andmouthwashes comprising the active agent in a suitable liquid carrier.

For topical application to the skin, compounds of general formula (I) or(II) may be made up into a cream, ointment, jelly, solution orsuspension etc. Cream or ointment formulations that may be used for thedrug are conventional formulations well known in the art, for example,as described in standard text books of pharmaceutics such as the BritishPharmacopoeia.

Compounds of general formula (I) or (II) may be used for the treatmentof the respiratory tract by nasal, bronchial or buccal administrationof, for example, aerosols or sprays which can disperse thepharmacological active ingredient in the form of a powder or in the formof drops of a solution or suspension. Pharmaceutical compositions withpowder-dispersing properties usually contain, in addition to the activeingredient, a liquid propellant with a boiling point below roomtemperature and, if desired, adjuncts, such as liquid or solid non-ionicor anionic surfactants and/or diluents. Pharmaceutical compositions inwhich the pharmacological active ingredient is in solution contain, inaddition to this, a suitable propellant, and furthermore, if necessary,an additional solvent and/or a stabiliser. Instead of the propellant,compressed air can also be used, it being possible for this to beproduced as required by means of a suitable compression and expansiondevice.

Parenteral formulations will generally be sterile.

Typically, the dose of the compound will be about 0.01 to 100 mg/kg; soas to maintain the concentration of drug in the plasma at aconcentration effective to inhibit PGD₂ at the CRTH2 receptor. Theprecise amount of a compound of general formula (I) or (II) which istherapeutically effective, and the route by which such compound is bestadministered, is readily determined by one of ordinary skill in the artby comparing the blood level of the agent to the concentration requiredto have a therapeutic effect.

Compounds of general formula (I) or (II) may be used in combination withone or more active agents which are useful in the treatment of thediseases and conditions listed above, although these active agents arenot necessarily inhibitors of PGD₂ at the CRTH2 receptor.

Therefore, the pharmaceutical composition described above mayadditionally contain one or more of these active agents.

There is also provided the use of a compound of general formula (I) or(II) in the preparation of an agent for the treatment of diseases andconditions mediated by CRTH2 receptor agonists, especially PGD₂, whereinthe agent also comprises an additional active agent useful for thetreatment of the same diseases and conditions.

These additional active agents may be other CRTH2 receptor antagonistsor may have a completely different mode of action. They include existingtherapies for allergic and other inflammatory diseases including:

Suplatast tosylate and similar compounds;

β₁ to β₄ adrenoreceptor agonists such as metaproterenol, isoproterenol,isoprenaline, albuterol, salbutamol, formoterol, salmeterol,terbutaline, orciprenaline, bitolterol mesylate and pirbuterol ormethylxanthanines such as theophylline and aminophylline, mast cellstabilisers such as sodium cromoglycate or muscarinic receptor (M1, M2or M4) antagonists;

antihistamines, for example histamine H₁ receptor antagonists such asloratidine cetirizine, desloratidine, fexofenadine, astemizole,azelastine and chlorpheniramine or histamine H₂ or H₄ receptorantagonists;

α₁ and α₂ adrenoreceptor agonists such as propylhexedrine phenylephrine,phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride,oxymetazoline hydrochloride, tetrahydrozoline hydrochloride,xylometazoline hydrochloride and ethylnorepinephrine hydrochloride;

insulin-like growth factor (IGF-1) mimetics;

matrix metalloprotease (MMP) inhibitors, for example inhibitors ofstromelysins, collagenases gelatinases and aggrecanase, especiallycollagenase-1, collagenase-2, collagenase-3, stromelysin-1,stromelysin-2, stromelysin-3 and MMP-12;

modulators of chemokine receptor function, for example CCR1, CCR2,CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11(for the C—C family) or CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for theC—X—C family) and CX₃CR1 for the C—X₃—C family;

antiviral agents such as Viracept, AZT, acyclovir and famiciclovir andantisepsis compounds such as Valant;

cardiovascular agents, for example calcium channel blockers, lipidlowering agents such as statins, fibrates, beta-blockers, ACEinhibitors, Angiotensin-2 receptor antagonists and platelet aggregationinhibitors;

CNS agents, for example antidepressants such as sertraline,anti-Parkinsonian drugs such as deprenyl, L-dopa, Requip, Mirapex, MAOBinhibitors such as selegine and rasagiline, comP inhibitors such asTasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists,nicotine antagonists, Dopamine agonists and inhibitors of neuronalnitric oxide synthase and anti-Alzheimer's drugs such as donepezil,tacrine, COX-2 inhibitors, propentofylline or metryfonate;

Tryptase inhibitors;

Platelet activating factor (PAF) antagonists;

Interleukin converting enzyme (ICE) inhibitors;

IMPDH inhibitors;

Adhesion molecule inhibitors including VLA-4 antagonists;

Cathepsins;

MAP kinase inhibitors;

Glucose-6-phosphonate dehydrogenase inhibitors;

Kinin-B₁ and B₂ receptor antagonists;

Anti-gout agents such as colchicine;

Xanthine oxidase inhibitors such as allopurinol;

Uricosuric agents, such as probenecid, dulfinpyrazone and benzbromarone;

Growth hormone secretagogues;

Transforming growth factor beta (TGFβ);

Platelet-derived growth factor (PGDF)

Fibroblast growth factor e.g. basic fibroblast growth factor

Granulocyte macrophage colony stimulating factor (GM-CSF);

Capsaicin;

Tachykinin NK₁ and NK₃ receptor antagonists such as NKP-608C, talnetantand D-4418;

Elastase inhibitors such as UT-77 and ZD-0892;

Induced nitric oxide synthase inhibitors (iNOS);

Osteoporosis agents such as roloxifene, droloxifene, lasofoxifene orfosomax;

anticholinergic agents such as ipratropium bromide, tiotropium bromide,oxitropium bromide, pirenzepine and telenzepine;

leukotriene antagonists (LTB₄, LTD₄ and LTE₄ antagonists) such asphenothiazine-3-ones such as L-651,392, amidino compounds such asCGS-25019c, benzoxalamines such as ontazolast, benzene carboximidamidessuch as BIIL 284/260 and compounds such as zafirlukast, ablukast,montelukast, pranlukast, verlukast, RG-12525, Ro-245913, iralukast andBAY x 7195;

leukotriene biosynthesis inhibitors such as 5-lipoxygenase inhibitors or5-lipoxygenase activating protein (FLAP) inhibitors such as zileuton,ABT-761, fenleuton, tepoxalin, Abbott-79175,N-(5-substituted)-thiophene-2-alkylsolfonamides, 2,6-di-tert-butylphenolhydrazones, methoxytetrahydropyrans such as ZD2138, SB-210661,pyridinyl-substituted-2-cyanonaphthalene compounds such as L-739010,2-cyanoquinoline compounds such as L-746,530, indole and quinolinecompounds such as MK-591, MK-886 and BAY x 1005;

Phosphodiesterase inhibitors, including PDE4 inhibitors such as PDE4Dinhibitors;

anti-IgE antibody therapies such as omalizumab;

anti-infectives such as fusidic acid (particularly for the treatment ofatopic dermatitis);

anti-fungals such as clotrimazole (particularly for the treatment ofatopic dermatitis);

immunosuppressants such as tacrolimus and particularly pimecrolimus inthe case of inflammatory skin disease or alternatively FK-506,rapamycin, cyclosporine, azathioprine or methotrexate;

antiproliferative/antineoplastic drugs such as alkylating agents, e.g.cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan,chlorambucil, busulphan and nitrosoureas, antimetabolites, e.g.antifolates such as fluoropyrimidines such as 5-fluorouracil andtegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea,gemcitabine and paclitaxel;

antitumour antibiotics such as anthracyclines such as adriamycin,bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C,dactinomycin and methramicin;

antimitotic agents such as vinca alkaloids including vincristine,vinblastine, vindesine and vinorelbine and taxoides such as taxol andtaxostere and topoisomerase inhibitors such as epipodophyllotoxins likeetoposide and teniposide, amsacrine, topotecan and camptothecin;cytostatic agents such as antioestrogens such as tamoxifen, toremifene,raloxifene, droloxifene and iodoxyfene, oestrogen receptor downregulators such as fulvestrant, antiandrogens such as bicalutamide,flutamide, nilutamide and cyproterone acetate, LHRH antagonists oragonists such as goserelin, leuprorelin and buserelin, progestogens suchas megestrol acetate, aromatase inhibitors such as anastrozle,letrozole, borazole and exemestane and inhibitors of 5α reductase suchas finasteride;

agents which inhibit cancer cell invasion, for example metalloproteinaseinhibitors such as marimastat and inhibitors of urokinase plasminogenactivator receptor function;

inhibitors of growth factor function for example growth factorantibodies, growth factor receptor antibodies, e.g. the anti-erbb2antibody trastuzumab and the anti-erbb1 antibody cetuximab, farnesyltransferase inhibitors, tyrosine kinase inhibitors and serine orthreonine kinase inhibitors, for example inhibitors of the epidermalgrowth factor family such as EGFR family tyrosine kinase inhibitors suchasN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morphoinopropoxy)quinazolin-4-amine(gefitinib),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(CI 1033), or inhibitors of the platelet derived growth factor or thehepatocyte growth factor families;

antiangiogenic agents, particularly those which inhibit the effects ofvascular endothelial growth factor e.g. the anti-vascular endothelialcell growth factor antibody bevacizumab and also compounds that work byother mechanisms e.g. linomide, inhibitors of integrin αvβ3 funciton andangiostatin;

vascular damaging agents such as Combretastatin A4;

antisense therapies such as those which are directed to targets listedabove, e.g. ISIS 2503, an anti-ras antisense;

gene therapy agents, including agents for replacing aberrant genes suchas aberrant p53, or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzymepro-drug therapy), cytosine deaminase, thymidine kinase or a bacterialnitroreductase enzyme or agents for increasing patient tolerance tochemotherapy or radiotherapy such as multi-drug resistant gene therapy;

immunotherapy agents including in vivo and ex vivo approaches toincrease the immunogenicity of patient tumour cells such as transfectionwith cytokines such as IL2, IL4 or GMCSF, approaches to decrease T-cellanergy, approaches using transfected immune cells such ascytokine-transfected dentritic cells or approaches usingcytokine-transfected tumour cell lines or anti-idiotypic antiobodies;

corticosteroids such as prednisone, prednisolone, flunisolide,triamcinolone acetonide, beclomethasone dipropionate, budesonide,fluticasone propionate and mometasone furoate and hyaluronic acids suchas hyalgan and synvisc and P2X7 receptor antagonists;

drugs which promote Th1 cytokine response such as interferons, TNF orGM-CSF.

CRTH2 antagonists may also be combined with:

other antagonists of PGD₂ acting at other receptors such as DPantagonists;

inhibitors of phosphodiesterase type 4 such as cilonilast;

drugs that modulate cytokine production such as inhibitors of TNFαconverting enzyme (TACE) anti-TNF monoclonal antibodies, TNF receptorimmunoglobulin molecules, inhibitors of other TNF isoforms,non-selective COX-1/COX-2 inhibitors such as piroxicam, diclofenac,propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofenand ibuprofen, fenamates such as mefanamic acid, indomethacin, sulindacand apazone, pyrazolones such as phenylbutazone, salicilates such asaspirin; COX-2 inhibitors such as meloxicam, celecoxib, fofecoxib,valdecoxib and etoricoxib, low dose methotrexate, lefunomide,ciclesonide, hydroxychloroquine, d-penicillamine, auranofin orparenteral or oral gold.

drugs that modulate the activity of Th2 cytokines IL-4 and IL-5 such asblocking monoclonal antibodies and soluble receptors;

PPAR-γ agonists such as rosiglitazone; or with

anti-RSV antibodies such as Synagis (palivizumab) and agents that may beused to treat rhinovirus infection in the future e.g. interferon-betaand other interferons

In yet a further aspect of the invention, there is provided a productcomprising a compound of general formula (I) or (II) and one or more ofthe agents listed above as a combined preparation for simultaneous,separate or sequential use in the treatment of a disease or conditionmediated by the action of PGD₂ at the CRTH2 receptor.

The invention will now be described in greater detail with reference tothe following non limiting examples and the drawings in which:

FIG. 1 is a plot of blood concentration of Compound 1 versus time forrats dosed orally with 3 mg/kg of Compound 1.

FIG. 2 is a plot of blood concentration of Compound 2 versus time forrats dosed orally with 3 mg/kg of Compound 2.

FIG. 3 is a plot of blood concentration of Compound 3 versus time forrats dosed orally with 3 mg/kg of Compound 3.

FIG. 4 is a plot of blood concentration of Comparator Compound A versustime for rats dosed orally with 3 mg/kg of Compound A.

FIG. 5 is a plot of blood concentration of Comparator Compound B versustime for rats dosed orally with 3 mg/kg of Compound B.

FIG. 6 shows the effect of doses of 0.0001, 0.001, 0.01 and 0.1 μg/kg ofCompound 1 on DK-PGD₂ induced eosinophilia in rats.

FIG. 7 shows the effect of doses of 0.001, 0.01, 0.1 and 1.0 μg/kg ofCompound 2 on DK-PGD₂ induced eosinophilia in rats.

FIG. 8 shows the effect of doses of 0.001, 0.01, 0.1 and 1.0 μg/kg ofCompound 3 on DK-PGD₂ induced eosinophilia in rats.

FIG. 9 shows the effect of doses of 0.01, 0.1 and 1.0 mg/kg of CompoundA on DK-PGD₂ induced eosinophilia in rats.

FIG. 10 shows the effect of doses of 0.001, 0.01, 0.1 and 1.0 mg/kg ofCompound B on DK-PGD₂ induced eosinophilia in rats.

PREPARATION OF COMPOUNDS OF GENERAL FORMULA I

The compounds of Examples 1 to 3 were prepared according to thefollowing reaction schemes.

Example 1 Preparation of2-(5-fluoro-2-methyl-3-(2-(phenylsulfonyl)benzyl)-1H-indol-1-yl)aceticacid (Compound 1)

From commercial benzenesulfinic acid sodium salt and2-fluorobenzaldehyde.

a) Procedure I. (S_(N)Ar) to Yield 2-(phenylsulfonyl)benzaldehyde

To a solution of 2-fluoro benzaldehyde (5.00 ml, 47.6 mmol) in dimethylsulfoxide (45 ml) was added benzene sulfinic acid sodium salt (8.60 g,52.4 mmol) and the resulting mixture heated to 100° C. Upon heating thesulfinic acid salt dissolved. The solution was heated at 100° C. for 3days. The reaction was cooled to room temperature and water (50 ml)added. This mixture was extracted with ethyl acetate, the combinedorganic extracts were washed with saturated brine, dried over MgSO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography on silica eluting with 25% ethyl acetate:petroleum ether(40-60° C.) to 33% ethyl acetate:petroleum ether (40-60° C.) to give(4.12 g, 16.7 mmol, 35%). δ_(H) (300 MHz, d₆-DMSO) 10.68 (1H, s, CHO),8.26-8.17 (1H, m, Ar), 8.08-7.99 (2H, m, Ar), 7.99-7.89 (3H, m, Ar) and7.80-7.62 (3H, m, Ar).

b) Procedure E. (Reductive Alkylation) to Yield ethyl2-(5-fluoro-2-methyl-3-(2-(phenylsulfonyl)benzyl)-1H-indol-1-yl)acetate

To a solution of 2(5-fluoro-2-methyl-1H-indol-1-yl)acetic acid (1.29 g,1.49 mmol), 2-(phenylsulfonyl)benzaldehyde (1.50 g, 6.10 mmol) andtriethylsilane (4.30 ml, 27.0 mmol) in dichloromethane (40 ml) was addedtrifluoroacetic acid (1.25 ml, 16.5 mmol) dropwise under N₂ at 0° C.over 30 minutes. The reaction was warmed to room temperature and stirredfor 2 hours. Saturated aqueous sodium hydrogen carbonate solution wasadded and the product extracted with dichloromethane. The combinedorganic extracts were washed with saturated brine, dried over MgSO₄ andconcentrated in vacuo giving a brown oil which was triturated withpetroleum ether (40-60° C.) to give a white solid (1.34 g, 2.88 mmol52%).

δ_(H) (300 MHz, CDCl₃) 8.36-8.30 (1H, m, Ar), 8.00-7.93 (2H, m, Ar),7.68-7.52 (3H, m, Ar), 7.45-7.33 (2H, m, Ar), 7.05 (1H, dd, J 8.6 and4.3 Hz, Ar), 6.96-6.90 (1H, m, Ar), 6.82 (1H, td, J 9.1 and 2.7 Hz, Ar),6.24 (1H, dd, J 9.5 and 2.4 Hz, Ar), 4.76 (2H, s, NCH₂), 4.22 (2H, s,ArCH₂Ar), 4.21 (2H, q, J 7.1 Hz, CH₂CH₃), 2.14 (3H, s, CH₃) and 1.27(3H, t, J 7.1 Hz, CH₂CH₃).

c) Procedure F (Saponification) to Yield2-(5-fluoro-2-methyl-3-(2-(phenylsulfonyl)benzyl)-1H-indol-1-yl)aceticacid

To a stirred solution of ester product of step (b) (1.33 g, 2.86 mmol)in tetrahydrofuran (15 ml) was added a solution of aqueous KOH (500 mg,8.57 mmol) in water (15 ml). After 2 hours the tetrahydrofuran wasremoved under reduced pressure and the basic aqueous layer was washedwith ethyl acetate. The remaining aqueous layer was acidified with HCl(2N) and extracted with ethyl acetate. The combined organic extractswere washed with saturated brine, dried over MgSO₄ and concentrated invacuo giving a brown solid which was triturated with a mixture ofdiethyl ether and petroleum ether (40-60° C.) to give white solid (1.14g, 2.61 mmol 91%).

δ_(H) (300 MHz, d₆-DMSO) 13.00 (1H, bs, CO₂H), 8.26-8.20 (1H, m, Ar),7.99-7.93 (2H, m, Ar), 7.80-7.62 (3H, m, Ar), 7.55-7.48 (2H, m, Ar),7.34 (1H, dd, J 8.6 and 4.3 Hz, Ar), 6.93-6.87 (1H, m, Ar), 6.81 (1H,td, J 9.1 and 2.7 Hz, Ar), 6.18 (1H, dd, J 9.7 and 2.4 Hz, Ar), 4.95(2H, s, NCH₂), 4.14 (2H, s, ArCH₂Ar) and 2.06 (3H, s, CH₃). Tr=4.62 min(95%), m/z (M+H)⁺ 438.3.

Example 2 Preparation of2-(3-(2-(4-chlorophenylsulfonyl)benzyl)-5-fluoro-2-methyl-1H-indol-1-yl)aceticacid (Compound 2)

From commercial 2-(4-chlorophenylthio)benzaldehyde.

a) Procedure J. (Direct Oxidation) to Yield2-(4-chlorophenylsulfonyl)benzaldehyde

To a solution of 2-(4-chlorophenylthio)benzaldehyde (2.00 g, 8.00 mmol)in dichloromethane (20 mL) at 0° C. was added meta chloroperoxybenzoicacid (77% max, 5.40 g, 24.17 mmol) in portions over 15 minutes, thenwarmed to room temperature and stirred for 2 hours. Aqueous sodiummetabisulfite solution was added carefully until effervescence ceased.This solution was extracted with dichloromethane and the combinedorganic extracts were washed with NaOH (1N) then saturated brine, driedover MgSO₄ and concentrated in vacuo giving a white solid (1.05 g, 3.74mmol, 46%). δ_(H) (300 MHz, d₆-DMSO) 10.69 (1H, s, CHO), 8.25-8.18 (1H,m, Ar), 8.07-8.00 (2H, m, Ar), 8.00-7.90 (3H, m, Ar) and 7.81-7.64 (3H,m, Ar).

b) Procedure E. (Reductive Alkylation) to Yield ethyl2-(3-(2-(4-chlorophenylsulfonyl)benzyl)-5-fluoro-2-methyl-1H-indol-1-yl)acetate

δ_(H) (300 MHz, CDCl₃) 8.33-8.26 (1H, m, Ar), 7.89-7.82 (2H, m, Ar),7.53-7.46 (2H, m, Ar), 7.44-7.73 (2H, m, Ar), 7.06 (1H, dd, J 8.6 and4.3 Hz, Ar), 7.02-6.96 (1H, m, Ar), 6.84 (1H, td, J 9.1 and 2.7 Hz, Ar),6.33 (1H, dd, J 9.5 and 2.4 Hz, Ar), 4.76 (2H, s, NCH₂), 4.23 (2H, s,ArCH₂Ar), 4.22 (2H, q, J 7.2 Hz, CH₂CH₃), 2.16 (3H, s, CH₃) and 1.27(3H, t, J 7.2 Hz, CH₂CH₃).

c) Procedure F. (Saponification) to Yield2-(3-(2-(4-chlorophenylsulfonyl)benzyl)-5-fluoro-2-methyl-1H-indol-1-yl)aceticacid

δ_(H) (300 MHz, d₆-DMSO) 13.01 (1H, bs, CO₂H), 8.27-8.20 (1H, m, Ar),7.97-7.90 (2H, m, Ar), 7.74-7.67 (2H, m, Ar), 7.57-7.51 (2H, m, Ar),7.34 (1H, dd, J 8.7 and 4.3 Hz, Ar), 7.00-6.93 (1H, m, Ar), 6.81 (1H,td, J 9.4 and 2.6 Hz, Ar), 6.16 (1H, dd, J 9.8 and 2.6 Hz, Ar), 4.95(2H, s, NCH₂), 4.17 (2H, s, ArCH₂Ar) and 2.12 (3H, s, CH₃). Tr=4.04 min(96%), m/z (M+H)⁺ 472.0.

Example 3 Preparation of2-(5-fluoro-3-(2-(4-fluorophenylsulfonyl)benzyl)-2-methyl-1H-indol-1-yl)aceticacid (Compound 3)

a) Procedure A. (S_(N)Ar) to Yield 2-(4-fluorophenylthio)benzaldehyde

To a suspension of 4-fluorophenylthiol (0.86 ml, 8.06 mmol) and K₂CO₃(2.50 g, 18.12 mmol) in DMSO (5 ml) was added 2-fluorobenzaldehyde (1.00g, 8.06 mmol) under N₂ and the mixture heated at 100° C. for 3 hours.The reaction was cooled to room temperature and water (20 ml) added.This mixture was extracted with ethyl acetate, the combined organicextracts were washed with saturated brine, dried over MgSO₄ andconcentrated in vacuo to give a yellow solid (1.20 g, 5.17 mmol, 64%)

δ_(H) (300 MHz, d₆-DMSO) 10.23 (1H, s, CHO), 7.98 (1H, dd, J 7.3 and 1.7Hz, Ar), 7.63-7.49 (3H, m, Ar), 7.45-7.32 (3H, m, Ar) and 6.88 (1H, d, J7.7 Hz, Ar).

b) Procedure B. (Aldehyde Protection) to Yield(2-(dimethoxymethyl)phenyl)(4-fluorophenyl)sulfane

To a solution of the aldehyde product of step (a) (1.20 g, 5.17 mmol)and trimethylorthoformate (0.62 ml, 0.58 mmol) in anhydrous methanol (80ml) was added p-toluenesulfonic acid (0.10 g, 0.58 mmol) under N₂ andthe mixture stirred at room temperature for 72 hours. A solution ofsodium methoxide in methanol (0.12 ml, 25% sol, 0.58 mmol) was added andall solvent removed in vacuo giving a colourless oil (1.50 g). Nofurther purification was carried out.

δ_(H) (300 MHz, CDCl₃) 7.64 (1H, dd, J 7.3 and 2.0 Hz, Ar), 7.38-7.30(2H, m, Ar), 7.29-7.19 (2H, m, Ar), 7.15-7.10 (1H, m, Ar), 7.07-6.99(2H, m, Ar), 5.72 (1H, s, CH(CH₃)₂) and 3.37 (6H, s, CH(CH₃)₂).

c) Procedure C. (Oxidation) to Yield1-(dimethoxymethyl)-2-(4-fluorophenylsulfonyl)benzene

To a solution of the sulfide product of step (b) (1.50 g) indichloromethane (40 ml) was added 3-chloroperoxybenzoic acid (4.60 g,20.59 mmol) portionwise over 30 minutes at 0° C. The reaction was warmedto room temperature and stirred for 2 hours. Aqueous sodiummetabisulfite solution (50 ml) was added and the product extracted withdichloromethane. The combined organic extracts were washed with NaOH (50ml, 1N) followed by saturated brine, dried over MgSO₄ and concentratedin vacuo to give a yellow oil (1.40 g, 4.52 mmol 87% over 2 steps).

δ_(H) (300 MHz, CDCl₃) 8.11 (1H, dd, J 8.1 and 1.5 Hz, Ar), 7.85 (2H,dd, J 8.9 and 5.0 Hz Ar), 7.76 (1H, dd, J 7.9 and 1.5 Hz, Ar), 7.58 (1H,ddd J 7.8, 7.6 and 1.4 Hz, Ar), 7.47 (1H, ddd J 7.8, 7.6 and 1.4 Hz,Ar), 7.14-7.05 (2H, m, Ar), 6.12 (1H, s, CH(CH₃)₂) and 3.12 (6H, s,CH(CH₃)₂).

d) Procedure D. (Acetal Deprotection) to Yield2-(4-fluorophenylsulfonyl)benzaldehyde

To a solution of 1-(dimethoxymethyl)-2-(4-fluorophenylsulfonyl)benzene(1.40 g, 4.52 mmol) in tetrahydrofuran (20 ml) was added aqueoussulphuric acid (20 ml, 2% solution) and stirred at room temperature for12 hours. Solid K₂CO₃ was added until effervescence ceased and thesolution was basic. The solution was extracted with ethyl acetate, thecombined organic extracts were washed with saturated brine, dried overMgSO₄ and concentrated in vacuo to give a yellow solid (0.90 g, 340 mmol75%).

δ_(H) (300 MHz, CDCl₃) 10.85 (1H, s, CHO), 8.21-8.16 (1H, m, Ar),8.08-8.02 (1H, m, Ar), 7.97-7.90 (2H, m, Ar), 7.80-7.74 (2H, m, Ar) and7.27-7.19 (2H, m, Ar).

e) Procedure E. (Reductive Alkylation) to Yield ethyl2-(5-fluoro-3-(2-(4-fluorophenylsulfonyl)benzyl)-2-methyl-1H-indol-1-yl)acetate

δ_(H) (300 MHz, CDCl₃) 8.32-8.26 (1H, m, Ar), 8.00-7.90 (2H, m, Ar),7.43-7.37 (2H, m, Ar), 7.26-7.17 (2H, m, Ar), 7.06 (1H, dd, J 8.8 and4.3 Hz, Ar), 7.00-6.94 (1H, m, Ar), 6.84 (1H, td, J 9.1 and 2.6 Hz, Ar),6.32 (1H, dd, J 9.5 and 2.6 Hz, Ar), 4.77 (2H, s, NCH₂), 4.24 (2H, s,ArCH₂Ar), 4.22 (2H, q, J 7.2 Hz, CH₂CH₃), 2.16 (3H, s, CH₃) and 1.27(3H, t, J 7.2 Hz, CH₂CH₃).

f) Procedure F. (Saponification) to Yield2-(5-fluoro-3-(2-(4-fluorophenylsulfonyl)benzyl)-2-methyl-1H-indol-1-yl)aceticacid

δ_(H) (300 MHz, d₆-DMSO) 13.00 (1H, bs, CO₂H), 8.27-8.20 (1H, m, Ar),8.08-8.00 (2H, m, Ar), 7.60-7.45 (4H, m, Ar), 7.35 (1H, dd, J 8.7 and4.3 Hz, Ar), 6.99-6.93 (1H, m, Ar), 6.83 (1H, td, J 9.0 and 2.3 Hz, Ar),6.17 (1H, dd, J 9.8 and 2.6 Hz, Ar), 4.98 (2H, s, NCH₂), 4.18 (2H, s,ArCH₂Ar) and 2.13 (3H, s, CH₃). Tr=4.60 min (95%), m/z (M+H)⁺ 456.3

Example 4 Human Whole Blood Eosinophil Shape Change Assay

Compounds 1 to 3 were assayed for their effect on PGD2 inducedeosinophil shape change and were compared with Comparator Compounds A toG.

Comparator Compound A is(5-Fluoro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl)-acetic acid.

Comparator Compound B is[5-Fluoro-3-(4-methanesulfonyl-benzyl)-2-methyl-indol-1-yl]-acetic acid.

Comparator Compound C is2-{5-Fluoro-2-methyl-3-[4-(phenylsulfonyl)benzyl]-1H-indol-1-yl}aceticacid (the 4-regioisomer of Compound 1).

Comparator Compound D is2-{3-[4-(4-chlorophenylsulfonyl)benzyl]-5-fluoro-2-methyl-1H-indol-1-yl}aceticacid (the 4-regioisomer of Compound 2).

Comparator Compound E is2-{5-Fluoro-3-[4-(4-fluorophenylsulfonyl)benzyl]-2-methyl-1H-indol-1-yl}aceticacid (the 4-regioisomer of Compound 3).

Comparator Compound F is2-{5-Fluoro-2-methyl-3-[3-(phenylsulfonyl)benzyl]-1H-indol-1-yl}aceticacid (the 3-regioisomer of Compound 1).

Comparator Compound G is2-{3-[3-(4-chlorophenylsulfonyl)benzyl]-5-fluoro-2-methyl-1H-indol-1-yl}aceticacid (the 3-regioisomer of Compound 2).

Methods

Shape Change Assay in Whole Blood

Compounds (1 μl, 200×final concentration) were added directly to 200 μlwhole blood, mixed well and incubated for 15 min, 37° C., 5% CO₂. Afterthis time, cell shape was fixed by addition of 300 μl Cytofix™ buffer(BD Biosciences), 15 min on ice. 10 ml RBC lysis buffer was added to thefixed cells, incubated 5 min, at room temperature and centrifuged, 300×gfor 5 min. Supernatant (containing lysed red cells) was removed and thelysis step was repeated. Leukocytes were resuspended in 250 μl RPMI/10%FCS and shape change analysed by FACS. Eosinophils were gated out basedon their autofluorescence and 2000 eosinophil events were counted persample. Data were analysed in triplicate.

Results

The results for the eosinophil shape change assay are shown in Table 1.

All the compounds bound CRTH2 with a Ki of less than 0.012 μM. It can beseen from Table 1 that Compounds 1 to 3 all have excellent IC₅₀ valuesin this assay. Comparator Compound B has comparable activity in thisassay to Compounds 1 to 3 but the activity of Compound A is much lower.However, Comparator Compounds C to G, which are the para- andmeta-regioisomers of Compounds 1 to 3 have comparatively poor activityin this test (of the order of 10 to 1000 times lower than that ofCompounds 1 to 3).

TABLE 1 IC₅₀ Values for the Effect of Test Compounds on 10 nmPGD2-induced Eosinophil Shape Change Whole Blood IC₅₀ (μM) CompoundValue SEM n 1 0.005 0.003 3 2 0.002 0.001 3 3 0.006 0.003 3 A 0.1030.009 4 B 0.008 0.002 3 C 0.273 0.175 3 D 0.494 NA 1 E 0.071 0.008 2 F1.50 N/A 1 G 4.66 N/A 1

Example 5 Investigation of Pharmacokinetics of Compounds of GeneralFormula (I) Following Oral Administration in the Rat

Experimental Procedures

a) Weighing of Rats

Rats were weighed on the day of dosing.

b) Dose Preparation

The test material was prepared as a 0.3 mg/mL suspension in 1%carboxy-methyl-cellulose (CMC).

c) Dose Regimen

Three groups of 3 rats were dosed as follows:

Group No. Treatment Dose (mg/kg) Route 1 Compound 1 3 oral 2 Compound 23 oral 3 Compound 3 3 oral

d) Dose Administration

Doses were administered as a single oral dose using a gavage tube at aconstant dose volume of 10 mL/kg.

e) Blood Sample Collection

At each sampling time point blood samples (approximately 0.3 mL) wastaken from a catheter inserted into a lateral tail vein prior to thestart of the experiment. The final blood sample (approximately 2 mL)from each animal was taken by cardiac puncture under isofluraneanaesthesia following which the animal was killed by exsanguination.Blood samples were taken into individual heparinised containers. Bloodsamples were collected at the following times post-dose:

15, 30, 60, 120, 240, 360, 480, 720 minutes and 24 hours

Following collection, the blood samples were centrifuged (approximately10,000×g, 2 min at 4° C.) and the plasma stored as one aliquot atapproximately −20° C. pending analysis of drug concentrations byLC-MS/MS.

f) Sample Bioanalysis

The plasma samples were analysed for test material concentrations atBioDynamics using an LC-MS/MS method developed at BioDynamics.

Results

The pharmacokinetic profile of a compound is important as it illustrateshow much of a compound will remain in the body for how long and theexposure of a subject to a compound when administered orally.

The results for the blood concentrations of Compounds 1, 2, 3, A and Bare shown in Tables 2, 3, 4, 5 and 6 respectively.

A compound which is intended to be administered orally, will ideallyneed to be taken only once or twice daily as this reduces the burden onthe patient and thus increases patient compliance. Therefore, it isgreatly preferred that after 12 hours, the concentration of drugremaining in the blood is as at least as great as the IC₅₀ value for thecompound and preferably considerably higher than this. An even morefavourable pharmacokinetic profile is one in which the concentrationremaining in the blood after 24 hours is at least as great as the IC₅₀value for the compound and preferably considerably higher than this.

TABLE 2 Concentration of Compound 1 in blood (ng/mL) after oraladministration to rats at a dose of 3 mg/kg Time Concentration in Blood(ng/mL) (h) Male 4 Male 5 Male 6 Mean SD 0.25 1161.2 1496.0 1678.01445.1 262.1 0.5 2681.3 2792.4 3264.7 2912.8 309.8 1 3835.5 3895.34262.9 3997.9 231.4 2 4330.9 3454.7 4051.1 3945.6 447.5 4 1890.9 1046.51670.8 1536.1 438.0 6 1423.7 547.5 1183.1 1051.4 452.7 8 1099.9 404.7696.2 733.6 349.1 12 455.4 256.6 412.8 374.9 104.7 24 68.5 10.2 63.547.4 32.3

The results in Table 2 show that after 24 hours, the mean amount ofCompound 1 remaining in the blood was 47.4 ng/mL. The IC₅₀ of Compound 1in the whole blood eosinophil shape change assay is 5 nM (2.2 ng/ml) andis therefore ca. 21 times over the whole blood eosinophil shape changeIC₅₀ at 24 hrs. The results therefore show that Compound 1 isparticularly suitable for oral administration to a patient.

TABLE 3 Concentration of Compound 2 in blood (ng/mL) after oraladministration to rats at a dose of 3 mg/kg Time (h) Male 7 Male 8 Male9 Mean SD 0.25 1569.4 1297.7 1608.1 1491.7 169.1 0.5 2612.1 1770.22276.6 2219.6 423.8 1 2958.2 2367.1 3366.1 2897.1 502.3 2 2239.9 2536.92717.6 2498.1 241.2 4 1128.4 1319.1 1666.5 1371.3 272.8 6 519.6 368.31032.6 640.2 348.2 8 423.7 186.7 740.4 450.3 277.8 12 144.7 28.2 128.1100.3 63.0 24 60.5 0.0 0.0 ND 0.0

The results in Table 3 show that after 12 hours, the mean amount ofCompound 2 remaining in the blood was 100.3 ng/mL. The results at 24hours were less consistent and the mean was not determined at this time.The IC₅₀ of Compound 2 in the whole blood eosinophil shape change assayis 2 nM (0.9 ng/ml) and is therefore ca. 111 times over the whole bloodeosinophil shape change IC₅₀ at 12 hrs. The results therefore show thatCompound 2 is suitable for oral administration to a patient, althoughthe profile is not as favourable as that of Compound 1.

TABLE 4 Concentration of Compound 3 in blood (ng/mL) after oraladministration to rats at a dose of 3 mg/kg Time (h) Male 13 Male 14Male 15 Mean SD 0.25 835.8 1130.7 1337.2 1101.2 252.0 0.5 2056.6 2205.22487.5 2249.8 218.9 1 2487.6 3547.8 3393.7 3143.0 572.8 2 4320.6 3685.14221.0 4075.6 341.8 4 3132.0 2023.1 2053.8 2403.0 631.5 6 1333.7 995.01098.0 1142.2 173.6 8 1163.7 699.5 678.5 847.2 274.3 12 465.3 163.3201.1 276.6 164.5 24 38.2 0.0 10.1 16.1 19.8

The results in Table 4 show that after 24 hours, the mean amount ofCompound 3 remaining in the blood was 16.1 ng/mL. The IC₅₀ of Compound 1in the whole blood eosinophil shape change assay is 6 nM (2.7 ng/ml) andis therefore ca. 6 times over the whole blood eosinophil shape changeIC₅₀ at 24 hrs. The results therefore show that Compound 3 isparticularly suitable for oral administration to a patient.

The results in Table 5 show that after 24 hours, the mean amount ofCompound (A) remaining in the blood was 43.7 ng/mL. The IC₅₀ of Compound1 in the whole blood eosinophil shape change assay is 103 nM (35.8ng/ml) and is therefore ca. 1.2 times over the whole blood eosinophilshape change IC₅₀ at 24 hrs.

TABLE 5 Concentration of Compound (A) in blood (ng/mL) after oraladministration to rats at a dose of 3 mg/kg Time (h) Male 4 Male 5 Male6 Mean Stdev 0.25 139.1 153.9 68.3 120.4 45.8 0.5 425.6 388.4 256.3356.8 89.0 1 875.2 923.2 538.8 779.1 209.5 2 1415.1 1309.0 1013.6 1245.9208.1 4 923.1 820.5 827.0 856.9 57.5 6 404.3 514.8 432.6 450.6 57.4 8305.6 521.9 235.5 354.3 149.3 24 51.8 79.2 0.0 43.7 40.2

TABLE 6 Concentration of Compound (B) in blood (ng/mL) after oraladministration to rats at a dose of 3 mg/kg Time (h) Male 31 Male 32Male 33 Mean Stdev 0.25 91.8 113.6 57.3 87.6 28.4 0.5 121.2 165.7 132.1139.7 23.2 1 252.1 295.1 217.5 254.9 38.9 2 349.9 536.9 256.2 381.0142.9 4 179.4 485.2 184.9 283.2 175.0 6 128.3 292.2 125.8 182.1 95.4 872.1 184.5 84.7 113.8 61.6 12 36.5 31.0 14.5 27.3 11.4 24 0 0 0 0 0

The results in Table 6 show that after 12 hours, the mean amount ofCompound B remaining in the blood was 27.3 ng/mL. The IC₅₀ of Compound Bin the whole blood eosinophil shape change assay is 8 nM (3.0 ng/ml) andis therefore ca. 9.1 times over the whole blood eosinophil shape changeIC₅₀ at 12 hrs.

FIGS. 1 to 5 are plots blood concentration of compound versus time forrats dosed orally with 3 mg/kg of Compounds 1, 2, 3, A and Brespectively. They are therefore graphical representations of the dataset out in Tables 2 to 6.

The values for C_(max) (maximum blood concentration), T_(max), (time atwhich C_(max) occurs), AUC_(inf) (area under curve to infinity) andT_(1/2) (half life) taken from FIGS. 1 to 5 are set out in Tables 7 to11 for Compounds 1, 2, 3, A and B respectively.

The values for C_(max) and the AUC_(inf) represent the exposure of asubject to an oral dose of the compound. It is therefore preferred thatthe figures for both C_(max) and AUC should be as high as possible sothat exposure to the compound is maximised.

TABLE 7 PK Parameters for 3 mg/kg Compound 1 p.o Parameter Units Male 4Male 5 Male 6 Mean Cmax ng/mL 4331 3895 4263 4163 Tmax hours 2 1 1 1.3AUCinf ng/mL * hrs 23809 14846 21731 19328 T½ hours 4.11 3.07 4.59 3.6

TABLE 8 PK Parameters for 3 mg/kg Compound 2 p.o Parameter Units Male 7Male 8 Male 9 Mean Cmax ng/mL 2958.0 2537.0 3366.0 2954 Tmax hours 1.02.0 1.0 1.3 AUCinf ng/mL * hrs 13153 10179 15677 11666 T½ hours 6 2 23.7

TABLE 9 PK Parameters for 3 mg/kg Compound 3 p.o Parameter Units Male 13Male 14 Male 15 Mean Cmax ng/mL 4321 3685 4221 4076 Tmax hours 2 2 2 2.0AUCinf ng/mL * hrs 24379 17738 19110 21059 T½ hours 3.26 2.26 2.62 2.8

TABLE 10 PK Parameters for 3 mg/kg Compound (A) p.o Parameter Units Male4 Male 5 Male 6 Mean Cmax ng/mL 1415.1 1309.0 1013.6 1245.9 Tmax hours2.0 2.0 2.0 2.0 AUCinf ng/mL * hrs 8570.4 10429.2 5473.9 8157.8 T½ hours6.1 6.1 2.2 4.8

TABLE 11 PK Parameters for 3 mg/kg Compound (B) p.o Parameter Units Male4 Male 5 Male 6 Mean Cmax ng/mL 349.9 536.9 256.2 381.0 Tmax hours 2.02.0 2.0 2.0 AUCinf ng/mL * hrs 1831.4 3256.1 1505.1 2197.6 T½ hours 3.411.80 1.86 2.4

From Tables 7 to 11 it can be seen that Compounds 1, 2 and 3 have meanC_(max) values of 4163, 2954 and 4076 respectively. In contrast, themean values for Compounds A and B are only 1245.9 and 381.0.

The AUC_(inf) values for Compounds 1, 2 and 3 are 19238, 11666 and21059, while those for Compounds A and B are 8157.8 and 2197.6.

Thus the figures for both C_(max) and AUC_(inf) are significantly higherfor the compounds of the present invention than those for ComparatorCompounds A and B. It is clear from these results that subjects dosedorally with Compounds A and B would have much lower exposure to the drugthan subjects dosed orally with Compounds 1, 2 and 3.

The results from Examples 4 and 5 are summarised in Table 12, in whichthe Fold over IC₅₀ at 12 h is defined as the mean amount of compoundremaining in the blood at 12 hours in ng/ml divided by the IC₅₀ of thecompound in ng/ml. Similarly the fold over IC₅₀ at 24 h is defined as isdefined as the mean amount of compound remaining in the blood at 24hours in ng/ml divided by the IC₅₀ of the compound in ng/ml.

TABLE 12 Compound 1 2 3 A B IC₅₀ (μmol) 0.005 0.002 0.006 0.103 0.008IC₅₀ (ng/mL) 2.2 0.9 2.7 35.8 3.0 Fold over 170 111 102 ND 9.1 IC₅₀ at12 h Fold over 21 ND 6 1.2 0 IC₅₀ at 24 h C_(max) 4163 2954 4076 1246381 AUC_(inf) 19328 11666 21059 8158 2198

Table 12 shows that Comparator Compound A has a higher IC₅₀ thanCompounds 1, 2 and 3 and a lower value for fold over IC₅₀ at 24 hoursthan Compounds 1 and 3. The exposure of a subject to the drug after oraladministration as indicated by C_(max) and AUC_(inf) is significantlylower for Compound A than for any of Compounds 1 to 3.

Compound B has an IC₅₀ value which is comparable to that of Compounds 1,2 and 3. However, the fold over IC₅₀ at 12 and 24 hours is significantlyless favourable than that of any of Compounds 1 to 3 and the exposure ofa subject to the drug after oral administration as indicated by C_(max)and AUC_(inf) is significantly lower for Compound B than for any ofCompounds 1 to 3.

Comparator Compounds A and B each have some properties which arecomparable with those of Compounds 1, 2 and 3. However, taken as awhole, their properties are less favourable than those of the compoundsof the invention.

Example 6 Evaluation of Compounds of General Formula (I) as Inhibitorsof 13,14-dihydro-15-keto prostaglandin D2 (DK-PGD2)-Induced BloodEosinophilia in Rats

Protocol

The test compound was dissolved in DMSO and diluted with water to give afinal dosing volume of 2 ml/kg.

Female rats (175-250 g; UH colony) were dosed orally with test compound(or vehicle).

30 min after dosing all animals were anaesthetised with isoflurane.

Following induction of anaesthesia, animals receive an intracardiacinjection of 10 μg DK-PGD₂ in 0.3 ml heparinised (10 U/ml) saline.Control animals received an injection of 0.3 ml heparinised saline.

60 min after the intracardiac injection, animals were injected with anoverdose of pentobarbitone sodium and a blood sample was taken (intoheparin) by cardiac puncture while the rat was anaesthetised but notdead.

An aliquot of blood (100 μl) was added to Turk's solution and the totalleukocyte count determined with a haemocytometer.

A further aliquot of blood (500 μl) was mixed with an equal volume of 4%Dextran (mw 500,000) and the erythrocytes allowed to settle. A cytospinpreparation was made from the resulting leukocyte rich fraction.

Cytospin preparations were fixed with methanol (5 min) and stained withMay-Grunwald (5 min) and Giemsa (15 min) stains. Finally cytospins werewashed in phosphate buffer (pH6.8) and air dried.

Differential leukocyte counts were obtained from the cytospinpreparations.

Blood eosinophil numbers were determined from the total leukocyte countand the percentage eosinophils (differential count).

Experimental Design

Up to 12 animals were used in each experiment. Groups included:

Untreated controls

DK-PGD₂-induced eosinophilia, vehicle treated animals (positive control)

DK-PGD₂-induced eosinophilia, Compound 1; doses of 0.0001, 0.001, 0.01and 0.1 μg/kg p.o.

DK-PGD₂-induced eosinophilia, Compound 2; doses of 0.001, 0.01, 0.1 and1.0 μg/kg p.o.

DK-PGD₂-induced eosinophilia, Compound 3; doses of 0.001, 0.01, 0.1 and1.0 μg/kg p.o.

DK-PGD₂-induced eosinophilia, Compound A; doses of 0.01, 0.1 and 1.0mg/kg p.o.

DK-PGD₂-induced eosinophilia, Compound A; doses of 0.001, 0.01, 0.1 and1.0 mg/kg p.o.

Because it was impractical to generate sufficient data in any givenexperiment, data were obtained over a number of replicate experiments.Data from these replicate experiments were pooled, to provide at least 5animals in each group and a dose-response curve fitted following asignificance test (Mann Whitney) to determine whether or not DK-PGD₂caused a significant increase in blood eosinophils (GraphPad, Prism). Adifference between groups was taken to be significant when P<0.05. ED50values were calculated from the dose-response curve.

The results of these experiments are shown in FIGS. 6 to 10 and in Table13 below.

TABLE 13 Compound 1 2 3 A B Potency in inhibition of DK-PGD₂- 0.00250.010 0.010 37 17 induced blood eosinophilia (μg/ml)

It can be seen from Table 13 and FIGS. 6-10 that Compounds 1-3 areseveral thousand times more potent than Comparator Compounds A and B ininhibiting DK-PGD₂-induced blood eosinophilia in rats.

1. A compound of general formula (I)

wherein R is phenyl optionally substituted with one or more halosubstituents; or a pharmaceutically acceptable salt, hydrate, solvate,complex or prodrug thereof.
 2. A compound of general formula (II):

wherein R is phenyl optionally substituted with one or more halosubstituents; and R¹ is C₁-C₆ alkyl, aryl, (CH₂)_(m)OC(═O)C₁-C₆alkyl,(CH₂)_(m)N(R¹¹)₂, or CH((CH₂)_(m)O(C═O)R¹²)₂; m is 1 or 2; R¹¹ ishydrogen or methyl; R¹² is C₁-C₁₈ alkyl.
 3. A compound as claimed inclaim 1 or claim 2, wherein the phenyl group R is unsubstituted or issubstituted with a single halo substituent.
 4. A compound as claimed inclaim 3, wherein the halo substituent is fluoro or chloro.
 5. A compoundas claimed in claim 4, wherein the fluoro or chloro substituent is atthe 4-position of the phenyl group R.
 6. A compound selected from thegroup consisting of:2-{5-Fluoro-2-methyl-3-[2-(phenylsulfonyl)benzyl]-1H-indol-1-yl}aceticacid;2-{3-[2-(4-chlorophenylsulfonyl)benzyl]-5-fluoro-2-methyl-1H-indol-1-yl}aceticacid;2-{5-Fluoro-3-[2-(4-fluorophenylsulfonyl)benzyl]-2-methyl-1H-indol-1-yl}aceticacid; and the C₁-C₆ alkyl, aryl, (CH₂)_(m)OC(═O)C₁-C₆alkyl,(CH₂)_(m)N(R¹¹)₂, CH((CH₂)_(m)O(C═O)R¹²)₂ esters thereof; wherein m is 1or 2; R¹¹ is hydrogen or methyl; and R¹² is C₁-C₁₈ alkyl.
 7. A processfor the preparation of a compound of general formula (I) as claimed inclaim 1, the process comprising reacting with a base, a compound ofgeneral formula (II)

wherein R is as defined in claim 1 and wherein R¹ is C₁-C₆ alkyl. 8.(canceled)
 9. A method of treating a disease, disorder or condition,comprising administering to a patient in need of such treatment asuitable amount of a compound as claimed in claim 1 or claim 2, whereinthe disease, disorder or condition is selected from the group consistingof asthma, cough, acute and chronic rhinitis, nasal polyposis, acuteviral infection atopic dermatitis, contact hypersensitivity eczematousdermatitis, phyto dermatitis, photo dermatitis, sebhorroeic dermatitis,dermatitis herpetiformis, lichen planus, lichen sclerosis et atrophica,pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus,pemphigus, pemphigoid, epidermolysis bullosa urticaria, angioedema,vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata,male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome,erythema multiforme, cellulitis, panniculitis, cutaneous lymphomas,non-melanoma skin cancer, dysplastic lesions, blepharitisconjunctivitis, anterior and posterior uveitis, choroiditis, autoimmune,degenerative or inflammatory disorders affecting the retina,ophthalmitis; bronchitis, emphysema, bronchiectasis, farmer's lung,hypersensitivity pneumonitis, idiopathic interstitial pneumonias,complications of lung transplantation, vasculitic and thromboticdisorders of the lung vasculature, pulmonary hypertension, foodallergies, gingivitis, glossitis, periodontitis, oesophagitis,eosinophilic gastroenteritis, proctitis, pruris ani, celiac disease,food-related allergies, inflammatory bowel disease, ulcerative colitis,Crohn's disease, mastocytosis, other CRTH2-mediated diseases, autoimmunediseases, AIDS, leprosy, Sezary syndrome, paraneoplastic syndrome, mixedand undifferentiated connective tissue diseases, inflammatorymyopathies, polymalgia rheumatica, juvenile arthritis, rheumatic fever,vasculitides, Takayasu's arteritis, Churg-Strauss syndrome,polyarteritis nodosa, microscopic polyarteritis, temporal arteritis,myasthenia gravis, acute and chronic pain, neuropathic pain syndromes,neurodegeneration, central and peripheral nervous system complicationsof malignant, infectious or autoimmune processes, low back pain,familial Mediterranean Fever, Muckle-Wells syndrome, Familial Hibernianfever, Kikuchi disease, psoriasis, acne, multiple sclerosis, allograftrejection, reperfusion injury, chronic obstructive pulmonary disease,rheumatoid arthritis, Still's disease, ankylosing spondylitis, reactivearthritis, undifferentiated spondarthropathy, psoriatic arthritis,septic arthritis, infection-related arthopathies, bone disorders,osteoarthritis, acute and chronic crystal-induced synovitis, calciumpyrophosphate deposition disease, calcium paptite related tendonsyndrome, synovial inflammation, Behcet's disease, primary and secondarySjogren's syndrome, systemic sclerosis, and limited scleroderma,hepatitis, cirrhosis of the liver, cholecystitis, pancreatitis,nephritis, nephritic syndrome, cystitis, Hunner's ulcer, acute andchronic urethritis, prostatitis, epididymitis, oophoritis, salpingitis,vulvo-vaginitis, Peyronie's disease, erectile dysfunction, Alzheimer'sdisease, dementing disorders, pericarditis, myocarditis, inflammatoryand auto-immune cardiomyopathies, common cancers, fibrotic conditions,liver fibrosis, sarcoidosis, scleroderma, kidney fibrosis resulting fromdiabetes, fibrosis associated with RA, atherosclerosis, vasculitis,myocardial fibrosis resulting from myocardial infarction, cysticfibrosis, restenosis, systemic sclerosis, Dupuytren's disease, fibrosiscomplicating anti-neoplastic therapy, chronic infection, CNS fibrosisfollowing stroke and the promotion of healing without fibrotic scarring.10. (canceled)
 11. A pharmaceutical composition comprising a compound asclaimed in claim 1 or claim 2 together with a pharmaceutical excipientor carrier.
 12. A composition as claimed in claim 11 formulated fororal, rectal, nasal, bronchial, topical, vaginal or parenteraladministration.
 13. A composition as claimed in claim 11 furthercomprising one or more additional active agents useful in the treatmentof diseases and conditions mediated by PGD₂ or other agonists at theCRTH2 receptor.
 14. A composition as claimed in claim 13, wherein theadditional active agents are selected from the group consisting of:other CRTH2 antagonists, Suplatast tosylate, β₁ to β₄ adrenoreceptoragonists, methylxanthanines, mast cell stabilisers, muscarinic receptorantagonists, antihistamines, α₁ and α₂ adrenoreceptor agonists,insulin-like growth factor (IGF-1) mimetics, matrix metalloprotease(MMP) inhibitors, modulators of chemokine receptor function, antiviralagents, antisepsis compounds, cardiovascular agents, CNS agents,Tryptase inhibitors, Platelet activating factor (PAF) antagonists,Interleukin converting enzyme (ICE) inhibitors, IMPDH inhibitors,Adhesion molecule inhibitors, Cathepsins, MAP kinase inhibitors,Glucose-6-phosphonate dehydrogenase inhibitors, Kinin-B₁ and B₂ receptorantagonists, Anti-gout agents, Xantine oxidase inhibitors, Uricosuricagents, Growth hormone secretagogues, Transforming growth factor beta(TGFβ), Platelet-derived growth factor (PGDF), Fibroblast growth factor,Granulocyte macrophage colony stimulating factor (GM-CSF), Capsaicin,Tachykinin NK₁ and NK₃ receptor antagonists, Elastase inhibitors,Induced nitric oxide synthase inhibitors (iNOS), Osteoporosis agents,anticholinergic agents, leukotriene antagonists, leukotrienebiosynthesis inhibitors, Phosphodiesterase inhibitors, anti-IgE antibodytherapies, anti-infectives, anti-fungals, immunosuppressants,antiproliferative/antineoplastic drugs, antitumour antibiotics,antimitotic agents, cytostatic agents, oestrogen receptor downregulators, LHRH antagonists or agonists, progestogens, aromataseinhibitors, agents which inhibit cancer cell invasion, inhibitors ofgrowth factor function, farnesyl transferase inhibitors, tyrosine kinaseinhibitors, serine or threonine kinase inhibitors, antiangiogenicagents, vascular damaging agents, antisense therapies, gene therapyagents, immunotherapy agents, corticosteroids, hyaluronic acids, drugswhich promote Th1 cytokine response, other antagonists of PGD₂ acting atother receptors, inhibitors of phosphodiesterase type 4, drugs thatmodulate cytokine production, inhibitors of other TNF isoforms,non-selective COX-1/COX-2 inhibitors, COX-2 inhibitors, low dosemethotrexate, lefunomide, ciclesonide, hydroxychloroquine,d-penicillamine, auranofin, parenteral or oral gold, drugs that modulatethe activity of Th2 cytokines IL-4 and IL-5, PPAR-γ agonists, anti-RSVantibodies, and agents that may be used to treat rhinovirus infection.15. A process for the preparation of a pharmaceutical composition asclaimed in claim 11 comprising bringing a compound of general formula(I)

wherein R is phenyl optionally substituted with one or more halosubstituents; or a pharmaceutically acceptable salt, hydrate, solvate,complex or prodrug thereof; or a compound of general formula (II)

wherein R is as defined above; and R¹ is C₁-C₆ alkyl, aryl,(CH₂)_(m)OC(═O)C₁-C₆alkyl, (CH₂)_(m)N(R¹¹)₂, or CH((CH₂)_(m)O(C═O)R¹²)₂;m is 1 or 2; R¹¹ is hydrogen or methyl; R¹² is C₁-C₁₈ alkyl inconjunction or association with a pharmaceutically or veterinarilyacceptable carrier or vehicle.
 16. A method of treatment of a disease orcondition mediated by the action of PGD₂ or other agonists at the CRTH2receptor comprising administering a compound of general formula (I)

wherein R is phenyl optionally substituted with one or more halosubstituents; or a pharmaceutically acceptable salt, hydrate, solvate,complex or prodrug thereof; or a compound of general formula (II)

wherein R is as defined above; and R¹ is C₁-C₆ alkyl, aryl,(CH₂)_(m)OC(═O)C₁-C₆alkyl, (CH₂)_(m)N(R¹¹)₂, or CH((CH₂)_(m)O(C═O)R¹²)₂;m is 1 or 2; R¹¹ is hydrogen or methyl; R¹² is C₁-C₁₈ alkyl; and one ormore of the agents listed in claim 14 as a combined preparation forsimultaneous, separate or sequential administration.
 17. The method asclaimed in claim 9, further comprising administering an additionalactive agent useful for the treatment of diseases and conditionsmediated by PGD₂ or other agonists at the CRTH2 or DP receptor.
 18. Themethod as claimed in claim 17, wherein the additional active agent isselected from the group consisting of other CRTH2 antagonists, Suplatasttosylate, β₁ to β₄ adrenoreceptor agonists, methylxanthanines, mast cellstabilisers, muscarinic receptor antagonists, antihistamines, α₁ and α₂adrenoreceptor agonists, insulin-like growth factor (IGF-1) mimetics,matrix metalloprotease (MMP) inhibitors, modulators of chemokinereceptor function, antiviral agents, antisepsis compounds,cardiovascular agents, CNS agents, Tryptase inhibitors, Plateletactivating factor (PAF) antagonists, Interleukin converting enzyme (ICE)inhibitors, IMPDH inhibitors, Adhesion molecule inhibitors, Cathepsins,MAP kinase inhibitors, Glucose-6-phosphonate dehydrogenase inhibitors,Kinin-B₁ and B₂ receptor antagonists, Anti-gout agents, Xantine oxidaseinhibitors, Uricosuric agents, Growth hormone secretagogues,Transforming growth factor beta (TGFβ), Platelet-derived growth factor(PGDF), Fibroblast growth factor, Granulocyte macrophage colonystimulating factor (GM-CSF), Capsaicin, Tachykinin NK₁ and NK₃ receptorantagonists, Elastase inhibitors, Induced nitric oxide synthaseinhibitors (iNOS), Osteoporosis agents, anticholinergic agents,leukotriene antagonists, leukotriene biosynthesis inhibitors,Phosphodiesterase inhibitors, anti-IgE antibody therapies,anti-infectives, anti-fungals, immunosuppressants,antiproliferative/antineoplastic drugs, antitumour antibiotics,antimitotic agents, cytostatic agents, oestrogen receptor downregulators, LHRH antagonists or agonists, progestogens, aromataseinhibitors, agents which inhibit cancer cell invasion, inhibitors ofgrowth factor function, farnesyl transferase inhibitors, tyrosine kinaseinhibitors, serine or threonine kinase inhibitors, antiangiogenicagents, vascular damaging agents, antisense therapies, gene therapyagents, immunotherapy agents, corticosteroids, hyaluronic acids, drugswhich promote Th1 cytokine response, other antagonists of PGD₂ acting atother receptors, inhibitors of phosphodiesterase type 4, drugs thatmodulate cytokine production, inhibitors of other TNF isoforms,non-selective COX-1/COX-2 inhibitors, COX-2 inhibitors, low dosemethotrexate, lefunomide, ciclesonide, hydroxychloroquine,d-penicillamine, auranofin, parenteral or oral gold, drugs that modulatethe activity of Th2 cytokines IL-4 and IL-5, PPAR-γ agonists, anti-RSVantibodies, and agents that may be used to treat rhinovirus infection.